Monica Bayés, PhD • Departament de Ciències Experimentals i de la Salut

(Genetics), Universitat Pompeu Fabra, Barcelona, Spain Suzanne B. Cassidy, md • Director, Division of Human Genetics,

Department of Pediatrics, University of California at Irvine, Orange, CA Jamel Chelly, md • Institut Cochin, Laboratoire de Génétique et de

Physiopathologie des Retards Mentaux, Paris, France Rui M. Costa, PhD • Departments of Neurobiology, Psychiatry, and Psychology, and Brain Research Institute, University of California Los Angeles, Los Angeles, CA Joanna Dragich, bs • Department of Human Genetics, University of California Los Angeles School of Medicine, Los Angeles, CA Elisabeth M. Dykens, PhD • Neuropsychiatric Institute, University of California Los Angeles, Los Angeles, CA Ype Elgersma, PhD • Departments of Neurobiology, Psychiatry, and Psychology, and Brain Research Institute, University of California Los Angeles, Los Angeles, CA Gene S. Fisch, PhD • Senior Research Scientist, Division of Biostatistics, Department of Epidemiology and Public Health, and the Child Study Center, Yale University School of Medicine, New Haven, CT Jonathan Flint, md • Wellcome Trust Centre for Human Genetics,

University of Oxford, Oxford, UK Albert M. Galaburda, md • Emily Fisher Landau Professor of Neurology and Neuroscience, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA Jozef Gécz, PhD • Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital; Department of Paediatrics, Adelaide University, Adelaide, SA, Australia Richard J. Gibbons, DPhil, frcp • MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK Ben C. J. Hamel, md • Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, The Netherlands

Mark C. Hirst, DPhil • Molecular Genetics Section, Department of Biological Sciences, The Open University, Milton Keynes, England Luis A. Pérez Jurado, md, PhD • Departament de Ciencies Experimental i de la Salut (Genetics), Universitat Pompeu Fabra, Barcelona, Spain Julia C. Lewis, MRCPsych • Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UK Kieran C. Murphy, MMedSci, PhD, MRCPI, MRCPsych • Department of Psychiatry, Royal College of Surgeons in Ireland; Education and Research Centre, Beaumont Hospital, Dublin, Ireland Kathryn North, md, fracp • Department of Paediatrics, University of Sydney; Head, Neurogenetics Research Unit, Deputy Head, Institute of Neuromuscular Research, The Children's Hospital at Westmead, Westmead, Sydney, NSW, Australia Alan K. Percy, md • Departments of Pediatrics, Neurology, and Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL Nancy Ratner, PhD • Department of Cell Biology, Neurobiology, and

Anatomy, University of Cincinnati College of Medicine, Cincinnati, OH Julian R. Sampson, dm • Institute of Medical Genetics, University of Wales

College of Medicine, Cardiff, UK N. Carolyn Schanen, md, PhD • Head of Human Genetics Research, Nemours Research Programs, Alfred I. duPont Hospital for Children, Wilmington, DE

J. Eric Schmitt, md • Stanford Psychiatry Neuroimaging Laboratory,

Stanford University School of Medicine, Stanford, CA Alcino J. Silva, PhD • Departments of Neurobiology, Psychiatry, and Psychology, and Brain Research Institute, University of California Los Angeles, Los Angeles, CA Jean Steyaert, md • Department of Clinical Genetics, University of Maastricht, Maastricht, The Netherlands; Department of Child Psychiatry, University of Leuven, Belgium Takahito Wada, PhD • MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK

Introduction and Overview

The Genetics and Genomics of Neurobehavioral Disorders

Historical Introduction and Overview

Gene S. Fisch

1. introduction

Broadly speaking, the genetics and genomics of neurobehavioral disorders examine the causal relationship between genetic mutations on the one hand, and impaired development, particularly cognitive-behavioral development, on the other, and the neurobiological and neurophysiological functions that are disrupted in between. Although genetics and genomics form the biological bases of behavior, we do not assume that the biological components are the sole or necessarily the most important contributors to cognitive-behavioral development. During the past century, research by experimental psychologists have clearly demonstrated the extent to which environmental stimuli and the context in which they are presented are salient factors in behavioral growth and development, language, learning, and memory. Humans develop along many psychological dimensions behavior-ally, but this text focuses on known genetic anomalies and the cognitive-behavioral deficits that result in difficulties in learning and memory, problem-solving, language, and other associated limitations in psychomotor development. That is not to say no other aspects of behavior may be affected. Various forms of psychopathology may develop concomitantly with many neurodevelopmental genetic abnormalities. Children with the fragile X mutation manifest mild to severe mental retardation, but are also frequently hyperactive, inattentive, and impulsive. Children and adolescents with velo-

From: Contemporary Clinical Neuroscience: Genetics and Genomics of Neurobehavioral Disorders Edited by: G. S. Fisch © Humana Press Inc., Totowa, NJ

cardio-facial syndrome develop mild cognitive deficits but an unusually high proportion manifest schizophrenia.

2. COGNITIVE FUNCTION, INTELLIGENCE, AND GENETICS 2.1. Cognitive Ability and Intelligence

Any discussion of cognitive-behavioral impairment should begin with a description of cognitive-behavioral ability, and that involves the definition of intelligence. Recounting the famous remark by E.G. Boring, Jensen (1) stated that the operational definition of intelligence is what intelligence tests measure. Jensen continued, saying that problems arose only when more was attributed to intelligence than what was measured. Unfortunately, there is more than one point of view regarding the definition of intelligence, and that has been at issue for more than a century. In 1921, the editors of the Journal of Educational Psychology convened a symposium on intelligence and its measurement. Fourteen experts (among them, Edward L. Thorndike and Lewis Terman) provided nearly as many definitions, the central theme of which, according to Sternberg (2) was the ability of an individual to adapt to the environment. Sixty five years later, Sternberg and Detterman (3) convened a second symposium consisting of 24 experts who reiterated the earlier idea of adaptation. On the other hand, Sattler (4) highlighted 10 definitions provided by psychologists dating from Binet and Simon (5) through Sternberg (6) and, although many agreed that adaptation to the environment was a core component, not all included it as part of their definition. Some definitions emphasize the ability to learn. For example, Spearman (7) said that intelligence was "a special case ... of educing either relations or correlates." Others define intelligence as the ability to think abstractly. For example, Wechsler (8) defined intelligence as "the global capacity ... to act purposefully, to think rationally ..." More recently, Baroff and Olley (9) argued that intelligence is composed of three factors: practical problem solving, verbal ability, and social intelligence. However, Snyderman and Rothman (10) who asked more than 1000 experts in psychology, in fields related to psychology, and in genetics to define intelligence, found that these authorities nearly unanimously agreed otherwise. Experts said the three major components of intelligence were problem-solving ability, abstract reasoning, and the capacity to acquire knowledge.

2.1.1. A Brief Historical Survey of the Concept of Intelligence

The difficulty in defining intelligence has not been confined to 20th century psychology. Historically, the earliest conceptualizations of intelligence likely predate the notions espoused by Plato and the Socratic philosophers of the 5th century BC which involve the structure of mental processes. Plato argued that all knowledge was inborn and teaching merely extracted that which was already known. Aristotle, one of Plato's students, held a somewhat different point of view. According to Aristotle, humans, unlike other animals, had three internal senses or mental faculties with which to interpret the externally sensed universe: common sense, memory, and imagination (11).

As with its definition, localization of intellectual function has also proved problematic. In the 11th century, Abu Ibn Sina, the great Muslim physician also known as Avicenna, contended that there were three faculties of function in the body, one of which, the nervous faculty, was centered in the brain (12). Ibn Sina, an adherent of Aristotle's philosophy, updated the Aristotelian point of view, contending that the internal senses could be located in various brain regions. By the 15th century, physicians had extended Sina's model by adding a fourth internal sense, estimation. However, within the next 100 years, Vesalius, who actually dissected the human body, showed that these notions of brain localization were incorrect. Nonetheless, the idea of localization of brain function and its relationship to intelligence would resurface in the early part of the 19th century.

In the late 18th-early 19th century, Franz Gall revived the notion of brain function previously held by the post-Aristotlean physicians. Specifically, Gall argued that all mental activities proceeded from the brain, that brain was the organ for the mind and, like Avicenna before him, that individual mental faculties resided in different parts of the brain. Those portions of brain that were well developed would be larger than those that had evolved less favorably. Physionomically, these regions would emerge as bumps and depressions on the skull. Gall's theory of mind, brain and behavior—phrenology—was the first to argue that cranial prominence, which could be observed and measured, varied in size according to the magnitude of the cortical region beneath it. The size of the cortical region was, in turn, related to some innate mental faculty manifested at the behavioral level. Later in the 19th century, physiologists such as Flourens and Hughlings Jackson would find the Gallian notion of localization of brain function without merit. However, phrenology and craniometry flourished in the early to mid-19th century, particularly in anthropology and genetics, lending credence to some of the most egregious forms of racism and sexism Western society would encounter.

Craniometry was applied to collateral areas of research, specifically anthropology, by way of the physician and surgeon, Paul Broca, who founded the Anthropological Society of Paris in 1859 (13). Broca was the first to observe that patients with speech dysfunctions exhibited brain damage in similar regions of the left frontal lobe. Although he rejected phrenology, Broca's researches provided support for the notion that a language faculty resided in part of the brain. He also believed that brain size was related to intellect. Unfortunately, his beliefs about brain function would also provide a scientific foundation for racism and sexism. Broca stated that "In general, the brain is larger ... in men than in women, in eminent men than in men of mediocre talent, in superior races than in inferior races" (13). Ironically, Gall's brain weighed only 1198 grams, much smaller in size than that of the average European (1300-1400 g). Indeed, many of the anthropometric measures used to establish intellectual, racial or gender superiority, especially brain volume, were found to be flawed or even fraudulent (13).

2.2. Heredity and the Assessment of Intelligence

In addition to the discord created by a lack of agreement on the definition of intelligence, there is the matter of how one measures a nonphysical attribute. Craniometry had been one quantitative inferential approach, but its popularity had waned toward the end of the 19th century. Another, more sustainable approach was developed by Francis Galton. Galton, Charles Darwin's nephew, was keenly interested in quantitation and measurement, particularly as related to human features. In Hereditary Genius, Galton acknowledged the extent to which the Belgian statistician, Quetelet, influenced his own interests in statistics and measurement (14). Quetelet, in addition to his contributions to economics, applied Gauss' Theory of Errors to account for the variability and frequency distribution of adults' heights. Galton also investigated human attributes such as beauty, moral quality, socioeconomic status, ethnicity, the anthropometric measurements from craniometry and sensory processes (e.g., reaction time), and how these features could be related to intelligence (4,13,15). Galton adapted Quetelet's application of the normal distribution of errors to his own concept of mental ability and intelligence (14), the consequences of which continue to affect present day psychometrics, as well as researchers' efforts to estimate the prevalence of individuals with mental retardation (MR). It should be noted that the assumption of a Gaussian or normal distribution of frequencies as an appropriate model of psychological characteristics has never been satisfactorily demonstrated (15).

As a result of his seminal efforts in statistics, psychological measurement, and genetics, Galton engendered several important principles for the formal development of psychometrics and the rise of IQ testing. Galton was first to introduce the twin concepts of general mental ability and specific aptitude. These two "factors" of intelligence would eventually find favor in the early 20th century work of Charles Spearman. Like his predecessor, Spearman's "monarchic" (a single or unitary) theory of intelligence posited that mental processes could be subsumed principally under a common factor, g, and secondarily under factors specific to individual processes, s. Spearman contended that g represented mental energy used by the entire cortex and possibly the nervous system as well (16).

Spearman's (17) application of factor analysis to develop a two-factor theory of intelligence laid the foundations for later, more complex factor-analytic approaches. Thorndike (18) postulated that intelligence was formed by clusters of abilities connected to one another. Thurstone (19) devised a method of factor analysis showing that intelligence was composed of many factors. Guilford (20) devised a three-dimensional structure organizing intellect. Other quantitative psychologists conceived of intelligence as composed of two major components: fluid (nonverbal) and crystallized (culture-specific) abilities (21,22). Later, Gustaffson (23) would add a third factor to this two-factor model, visualization. A more complete survey of factor-analytic theories of intelligence can be found in Sattler (4).

At about the time Spearman was developing his two-factor theory, Alfred Binet had begun to test intelligence in French schoolchildren. Earlier, Binet had studied the relationship between craniometry and intelligence and found it wanting (13). Binet, along with his collaborator, Theodore Simon, were commissioned by the French educational system to devise a means by which to differentiate generally educable children from those who required special means. Accordingly, Binet and Simon set about collecting many different types of test items (24). Some items were related to vocabulary, some related to visual discriminations, some related to memory, some related to quantitative skills, that would satisfy four essential features that continue to form a basis for psychometric testing: (1) that items measure ability related to intellect; (2) that items be ordered by degree of difficulty; (3) that items be age-related; and (4) that items be standardized (25).

Interestingly, despite the many differences in conceptualization, IQ tests based on any of the aforementioned factor-analytic approaches produce remarkably similar results. The age range of the WISC-R overlaps the WPPSI from 6 to 6 1/2 years, and the Full Scale IQ scores from each test generated by a sample of 6-year-olds are highly correlated (r = .82). Median correlations between the WISC-R Full scale and the K-ABC Mental Processing Composite are also high (r = .70; 4). Composite IQ scores from the WISC-R and Stanford-Binet (4th Edition) are also highly correlated (r = .69 to r = .83), particularly among learning disabled and mentally retarded children (26). This is likely due to the many high positive correlations obtained from the various subtests that constitute specific factors, whether they are verbal or nonverbal, abstract/visual, quantitative, or associated with visual or auditory features of short-term memory.

The notion of a single score to represent intelligence, the intelligence quotient or IQ score, was generated by Lewis Terman (27). Terman was concerned about Binet's use of the term "mental age" and its relationship to chronological age in the testing procedure. Binet used mental age (MA) as the point at which a student could no longer produce correct responses, given the child's chronological age (CA). Terman, however, argued that calculating the difference between, for example, a 6-year-old child performing at the level of a 3-year-old is strikingly different from a 12-year-old performing at the 9-year-old level. Terman adapted the term "mental quotient" from Stern (28), contending that "this value expresses not the difference, but the ratio of mental to chronological age, and thus is partially independent of the absolute magnitude of chronological age" (cf. 4). Terman called his ratio, MAv CA, the "intelligence quotient" or, as it has come to be known, IQ, and composite intelligence test scores typically have been referred to as IQ ever since.

2.3. Mental Retardation and Intelligence

2.3.1. A Brief History

The earliest references to MR date back more than 3500 years, but systematic evaluation and training of individuals with MR is a relatively recent phenomenon, and associated with the post-Renaissance Age of Enlightenment of the late 18th, early 19th century (cf. 12) for a comprehensive historical review). Historically, individuals with MR were not treated well by the societies into which they were born. One means of inferring the manner in which individuals with MR were treated is to examine the Termanology used to describe them. The term "idiot" is derived from the Greek and was reserved for individuals unable to participate in the public forum, whereas "imbecile" is derived from the Latin and refers to a small stick indicative of frailty (29). It has been asserted that both the Greeks and Romans practiced infanticide as a means of dealing with babies born with physical and/or developmental disabilities (12).

The earliest attempts to train individuals with MR have been attributed to Jean M.G. Itard and his efforts to educate a 12-year-old boy named Victor of Aveyron, a putatively feral child (30-33). Itard, who believed that Victor's psychosocial development had been stunted, began an intensive program to civilize him. Although his successes were limited, Itard was able to train Victor to recognize letters of the alphabet, develop a small receptive language, to name several objects, and make fine motor discriminations (30).

Edouard Seguin, a former student of Itard, went on to develop his own "physiological treatment" to stimulate the nervous system so that a child with mental deficits could develop physically and intellectually. Every child was evaluated individually, and training exercises were based on the strengths and weaknesses observed in each, not unlike the extensive regimens employed currently by applied behavior analysts. Johann Guggenbuhl, a physician contemporaneous with Sequin and who established a facility in Abendberg, Switzerland, primarily treated children with cretinism. He claimed to cure them of their MR, but when his facility was examined by outside experts, the treatments were found ineffective. Until then, Guggenbuhl enjoyed a brief notoriety, and Samuel G. Howe, who visited him, returned to Massachusetts to establish an experimental program based on his teachings for individuals with MR (32). Seguin's greater effect in the United States was due in part to his emigration to New York in 1852. Earlier, Horace Mann had met Seguin in Paris, as did Hervey Wilbur and James Richard, all of whom went on to establish special education programs for the mentally retarded in the United States (34). In 1876, Seguin, Wilbur and Richard, along with several others, established the first professional association for individuals with MR.

Often, individuals with MR were conflated by the general public with persons suffering from mental health disorders. This resulted partly from the fact that individuals with MR were protected by the so-called Lunacy Acts passed in England centuries earlier (35). Recent surveys suggest, however, that individuals with MR are at increased risk for developing maladaptive behavior and other forms of psychopathology (36). This may account for some of the early findings by Goddard (37) in which the Kallikak family was described as prone to certain forms of criminal and maladaptive behavior; or other studies in which alcoholism and/or criminal activity were segregating (30,38,39).

2.4. Genetics and Intelligence

The link between genetics and intelligence was first clearly articulated by Galton (14), who later coined the term "eugenics" and reiterated "the practicability of supplanting inefficient human stock by better strains" (40). Galton also referred to his study of twins and the "vast preponderating effect of nature over nurture" (40). Statistical models for heritability estimates were subsequently devised by Fisher (41) and are at the core of ongoing nature-nurture debates, that is, the extent to which heredity and environment affect cognitive ability as reflected in the IQ score. Sattler (4) notes that differences in the percent of variance in IQ score accounted for by genetics ranges from 30% to 50%. However, Goldstein and Reynolds (42) state the range is much broader, that heritability of IQ can be as small as 20% or as large as 80%, depending on the model employed.

The heritability (and stability) of IQ is central to psychometric testing, although Binet not only questioned the utility of a single IQ score, but also declined to make use of it as a measure of inborn ability (13). Also, although some prominent geneticists and statisticians continued to propose more and complex statistical models of inherited intelligence (43,44), others would find fault with their respective methodologies (45,46) or data (15,46,47). Currently, the statistical models and data used to support the heritability of intelligence are, at best, controversial.

The concept of MR as represented by the lower tail of a frequency distribution of IQ scores is derived from a statistical formulation used in quantitative psychology and the presumed normal distribution of individual abilities. Developmental psychologists were saddled with the psychometric point of view until Piaget, who had worked with Binet, left to develop his own qualitative developmental psychology. Binet and Simon were concerned about how to evaluate correct responses; but Piaget, who was dissatisfied with this formulation, became interested in the types of incorrect responses children made and how remarkably similar those errors were at specific ages. Piaget conceived of human development as unfolding through several consecutive stages, that children pass through the same stages in the same sequence, and have similar intellectual structures (48). Piaget's theories of child development would later be taken up by Zigler (49,50) and his colleagues who would also differentiate familial MR from organic MR.

2.5. Genetics and Mental Retardation

Organic forms of MR were first identified clinically in the mid 19th century by J. Langdon Down (12). Down, along with other physicians of his time, for example, William Ireland, P.M. Duncan, and W. Millard, were seeking to classify MR according to its severity, phenotype, and possible etiology. Down's text, The Mental Affections of Children and Youth (1887), proposed three types of MR: congenital, accidental, and developmental (51). The etiology of those categorized as congenital MR were primarily genetic in origin and classified according to ethnic features: Negroid, Mongoloid, and so on. It has been argued that, as a self-described liberal, Down's ethnic classification was not intentionally racist (12). However, Down stated that many individuals with congenital MR exhibited anatomical features lacking in their parents but associated with the "lower races." Given the tenor of his time and the extent to which anthropometry was used to assess intelligence, one would be hard-pressed not to consider his remarks as at least tainted with racism. As an example: "The boy's aspect is such that it is difficult to realize that he is the child of Europeans, but so frequently are these characters presented, that there can be no doubt that these ethnic features are the result of degeneration" (13). Although the genotype for this disorder, trisomy 21, was identified in 1959, the term mongolism persisted until only recently, when it was renamed Down syndrome.

The putative role heredity played in MR was widely believed by many who studied individuals with developmental disorders. Many physicians reasoned that alcoholism was caused by hereditary factors (48). Others attributed criminality to heredity, as in the case of the"Jukes" family (52,53). The "Kallikak" family (37) was also frequently cited. It should be noted, however, that Gould (13) discovered the photographs used to depict the disordered features of several members of the Kallikak family, including that of Deborah Kallikak, had been retouched around the eyes and mouth to give them a more insidious appearance.

Although identification of many genetic causes of MR would have to await the cytogenetic and molecular genetic revolutions of the mid-to-late 20th century, many causes and clinical forms of the disorder were recognized by the mid-to-late 19th, and early part of the 20th century. In the 19th century, for example, neurofibromatosis type 1 (NF1) was first described by von Recklinghausen in 1863; tuberous sclerosis was reported by Bourneville in 1880; and cretinism was associated with hypothyroidism by Curling in 1860 and Fagge in 1870. In the early middle part of the 20th century, microcephaly associated with dysmorphic craniofacial features was identified by Cornelia de Lange in 1933; phenylketonuria (PKU) was observed by Fölling in 1934; gonadal dysgenesis recognized by Turner in 1938; and trisomy 21 (Down's syndrome) discovered cytogenetically by Lejeune and his colleagues in 1959 (cf. 12).

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